葡萄糖生成酶PCK1化INSIG1/2用于脂质生成
Daqian Xu1,2, Zheng Wang3, Yan Xia4,5
1Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. xudaqian@zju.edu.cn.
Nature
|April 24, 2020
概括
激活的AKT在癌细胞中化PCK1,然后激活SREBP蛋白质,促进脂质生成,瘤生长和肝细胞癌 (HCC) 的不良预后.
科学领域:
- 分子生物学
- 癌症生物学
- 生物化学
背景情况:
- 癌细胞依靠增加的脂质生成来增殖,这种过程由固醇调节元素结合蛋白 (SREBPs) 中心调节.
- 通常通过INSIG蛋白,SCAP和内细胞网中的固醇组成的复合物来抑制SREBP的激活.
- 这种复杂的精确调节机制,特别是有关瘤信号的,仍然不完全理解.
研究的目的:
- 研究瘤信号传导,特别是激活的AKT在肝细胞癌 (HCC) 中调节SREBP激活和脂质生成中的作用.
- 阐明激活AKT影响INSIG-SCAP相互作用和随后的SREBP激活的分子机制.
主要方法:
- 使用人类肝细胞癌 (HCC) 细胞和小鼠模型.
- 使用特定抗体和细胞局部化研究研究了蛋白质酸化事件.
- 分析了INSIG蛋白和SCAP之间的相互作用.
- 评估了SREBP激活,与脂质发生相关的基因转录,细胞增殖和瘤发生.
- 与HCC患者的临床数据相关的分子发现.
主要成果:
- 在HCC细胞中激活的AKT在Ser90中酸化enolpyruvate carboxykinase 1 (PCK1).
- 化PCK1转移到内网并化INSIG1和INSIG2,破坏它们与SCAP的相互作用.
- 这种干扰导致SCAP-SREBP复合体转移到戈尔吉,SREBP激活,以及与脂质发生相关的基因表达增加.
- PCK1,INSIG1和INSIG2化与SREBP1核积累相关,并预测HCC的预后不佳.
- 这种途径的抑制抑制了小鼠的瘤生长.
结论:
- 通过PCK1依赖INSIG蛋白质的酸化,瘤性AKT信号激活了HCC中SREBP介导的脂质生成.
- 这一途径对HCC的瘤细胞增殖和瘤发生至关重要.
- PCK1的激酶活性被认为是SREBP激活,脂质生成和HCC发育的关键调节剂.
- 针对这种途径为HCC提供了潜在的治疗策略.
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